This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-OD(ORDR)-101: Pilot projects for prevention, early detection and treatment of rare diseases. Described is a Phase 2a, multi-site, open-label, dose-ranging, challenge-dechallenge-rechallenge activity, safety, and pharmacokinetic study of ataluren in patients with nonsense-mutation-mediated hemophilia A and B (HA/HB), rare and life-threatening genetic disorders. Ataluren is a novel, oral drug that promotes ribosomal read through of mRNA containing a nonsense mutation (premature stop codon). Preclinical testing in a nonsense-mutation-mediated animal model of HB has documented that ataluren induces production of full-length, functional human clotting factor IX (FIX) protein in the liver. Pharmacological proof of concept for ataluren readthrough of premature stop codons is documented by Phase 2a data in patients with nonsense-mutation-mediated cystic fibrosis and Duchenne muscular dystrophy;pivotal, controlled studies to confirm clinical benefit in these diseases are ongoing. The Phase 2a study will enroll ~24 adult male patients with severe, nonsense-mutation-mediated HA/HB. Enrollment will be stratified to ensure that e6 evaluable subjects with each type of hemophilia (HA and HB) are included. They will receive 5-, 5-, 10-mg/kg of ataluren 3 times per day (TID) at morning, midday, and evening doses for 14 days in Cycle 1;following an off-PTC124 period of 7 to 35 days, the same subjects will receive 20-, 20-, 40-mg/kg of ataluren TID at morning, midday, and evening doses for 14 days in Cycle 2. The primary objective of the study will be to determine with 0.90 power whether PTC124 provides pharmacological effect in HA/HB as measured by plasma clotting factor VIII (FVIII)/FIX activity. Secondary measures will include other assessments of disease activity;determinations of ataluren safety, compliance, and exposure;and documentation of the occurrence of any bleeding episodes or use of exogenous FVIII/FIX concentrate. This study could be initiated as early as 3Q2009 and is projected to be completed by 3Q2011. Development of ataluren comprises a novel therapeutic approach to the treatment of genetic disorders, coupling identification of patients with a specific type of genetic defect and application of a small-molecule, orally delivered, systemic therapy that has the potential to safely correct the phenotypic expression of that genetic defect. Patients with HA/HB whose disease is caused by a nonsense mutation almost always have a severe phenotype. Ataluren treatment could convert these patients from a severe to a moderate phenotype while sparing them the substantial risks, inconvenience, and expense associated with frequent intravenous infusions of FVIII/FIX concentrate. Successful achievement of study goals would support a registration- directed development program that could lead to regulatory approval of ataluren in patients with HA/HB. Severe hemophilia A and B (HA/HB) are disabling and life-threatening orphan disorders caused by a genetic defect. No treatments to correct this genetic defect are available. In previous studies in animals and humans, ataluren has shown the potential to treat the underlying cause of HA/HB in a subset of patients whose disease is caused by a specific type of genetic abnormality called a nonsense mutation. The goal of the planned clinical trial is to evaluate the activity and safety of ataluren. The intent is to generate adequate data to support the launch of a larger study and ultimately to obtain FDA approval of ataluren for the treatment of nonsense- mutation-mediated HA/HB, thereby addressing a major unmet medical need. PUBLIC HEALTH RELEVANCE: Severe hemophilia A and B (HA/HB) are disabling and life-threatening orphan disorders caused by a genetic defect. No treatments to correct this genetic defect are available. In previous studies in animals and humans, ataluren has shown the potential to treat the underlying cause of HA/HB in a subset of patients whose disease is caused by a specific type of genetic abnormality called a nonsense mutation. The goal of the planned clinical trial is to evaluate the activity and safety of ataluren. The intent is to generate adequate data to support the launch of a larger study and ultimately to obtain FDA approval of ataluren for the treatment of nonsense-mutation-mediated HA/HB, thereby addressing a major unmet medical need.